Administration of medicaments by vaporisation

ABSTRACT

A method of making a medicament which is a vapour comprising heating a composition to a temperature not exceeding 500° C. for a time of less than 10 seconds. The composition is non-volatile at 75° C. and generates a vapour free of pyrolysis products when heated in this way. The vapour is produced in a portion of air smaller than the mean respiratory tidal volume. A composition suitable for using in such a method is also disclosed.

Administration of medicaments via the respiratory tract is one of thefastest ways of producing a therapeutic effect. This route is widelyused for the administration of anaesthetics, bronchodilator(β-adrenergic agonists and parasympathetic antagonist) drugs,anti-asthmatic, analgesic, and smooth muscle relaxant drugs. Theapplicant has investigated the range of compounds that can be sodelivered, and has devised improvements to compositions and methods ofadministration via the respiratory tract.

Drugs are administered into the respiratory tract in a number of ways.General anaesthetics in the form of gases are given into the respiratorytract. Other agents such as glyceryl trinitrate and other nitrates andnicotine which are volatile at ambient room temperature can also begiven by inhalation. Administration via the respiratory tract is alsoemployed for a number of other agents such as corticosteroids andsympathomimetics for the treatment of asthma. The advantages of thisroute of administration are that:

-   (i) drugs that have a local action on the lining of the lungs have    immediate access to the mucus membrane of the lung. The barrier    separating air from the systemic circulation in the terminal    bronchioles is one to several cells thick and provides a rapid means    of absorption of drugs into the systemic circulation;-   (ii) where the medicament is given in the form of a suspension or    mist (aerosol) it is possible to control the area of the lung that    is reached;-   (iii) lungs have a good blood supply and absorption into the    systemic circulation is rapid;-   (iv) medication absorbed via the lungs is quickly distributed by the    heart and arterial system to major organs such as the brain and skin    without first passing through the liver. Drugs that are absorbed    from the gastrointestinal tract on the other hand, are taken into    the hepatic portal system are delivered first into the liver. In the    liver, a large proportion of the dose may be destroyed by this    so-called “first pass effect”.

There are many devices designed to produce either a fine particlesuspension or aerosol for administration of medications, which are notsoluble or volatile, into the respiratory tract.

Dry particle inhalers (DPIs) deliver a cloud of particles into the flowof air breathed in. To be effective the particles need to bestatic-free, and within a narrow range of size. The process of sizereduction may cause the particles to become electrostatically chargedand agglomerate together to larger particles.

Particles with mean dimensions greater that 15 microns have sufficientmass to hit the back of the throat when delivered from a conventionalaerosol dispenser. They therefore may miss being taken into therespiratory tract and are swallowed. The swallowed drug may still beeffective although the pharmacokinetics of its absorption and ultimatefate are different from material which is absorbed form the respiratorytract. Particles of mean size of 5-15 microns tend to be deposited highup in the bronchial tree where absorption is less efficient that fromthe terminal bronchioles. Between 2 and 5 microns the particles reachthe level of the bronchi and terminal bronchioles and exert theireffect. Below approximately 1 micron mean diameter Brownian movement isexhibited by the particles and a proportion of particles of this sizetend to be breathed out in the expired air.

Metered dose inhalers (MDIs) are aerosol presentations which typicallydeliver 5-200 μl of a solution of the drug that is broken up into a finespray. The restriction on size of particle is roughly the same as forDPIs.

However, the requirements on optimum sizes of particles both for DPIsand MDIs are illustrative, and considerable variation is experienced. Afactor which is important is that when delivered from a nozzle, underpressure generated by a propellant, the particle may change in size,particularly as it travels down the respiratory tract where the inspiredair has a high relative humidity.

The compositions and devices used to deliver medicaments into therespiratory tract are used at ambient room temperature. Surprisingly, ithas been found that compositions which are solids or gels at ambientroom temperature can be converted into a vapour under controlledconditions so that the vapour, when admixed with inspired air, can beused to deliver medicament to all parts of the respiratory tract.

The applicant hypothesised that some of the disadvantages of currentlyavailable inhalation devices could be overcome by producing a quantityof vapour from a portion of a composition at the time of use, anddiluting the vapour with inspired air.

Therefore, in a first aspect the invention provides a method of making amedicament which is a vapour comprising or consisting of at least onetherapeutic substance or a precursor thereof, which method comprisesheating a composition to a temperature not exceeding 500° C. for a timeof less than 10 seconds and thereby generating a vapour comprising orconsisting of at least one therapeutic substance or a precursor thereof,wherein the composition is non-volatile at 25° C. but is capable ofgenerating a vapour comprising at least one therapeutic substance or aprecursor thereof which is substantially free of any products ofpyrolysis when heated to a temperature not exceeding 500° C. for a timenot exceeding 10 seconds.

In a second aspect the invention provides a method of administering avapour or its condensate comprising or consisting of at least onetherapeutic substance or a precursor thereof by inhalation, which methodcomprises heating a composition to a temperature not exceeding 500° C.for a time not exceeding 10 seconds to generate a vapour comprising orconsisting of at least one therapeutic substance or a precursor thereofin a portion of air smaller than the mean respiratory tidal volume, andinhaling the vapour so-produced or its condensate in admixture withinspired air, wherein the composition is non-volatile at 25° C. but iscapable of generating a vapour comprising at least one therapeuticsubstance or a precursor thereof which is substantially free of anyproducts of pyrolysis when heated to a temperature not exceeding 500° C.for a time not exceeding 10 seconds.

This method may be used to administer a vapour or its condensate to ahuman or animal subject. In this context the term “mean respiratorytidal volume” refers to the mean respiratory tidal volume of the subjectto which the vapour, or its condensate, is administered. In humans tidalvolume will vary depending on the age, sex and health of the subject. Atypical tidal volume for a healthy adult male is in the region of 500ml. For any given subject, tidal volume may be easily measured usingtechniques well known in the art (e.g. using a spirometer).

In a third aspect the invention provides a composition formulated foradministration of a vapour or its condensate, which vapour comprises orconsists of at least one therapeutic substance or a precursor thereof,wherein the composition is non-volatile at 25° C. but is capable ofgenerating a vapour comprising at least one therapeutic substance or aprecursor thereof which is substantially free of any products ofpyrolysis when heated to a temperature not exceeding 500° C. for a timenot exceeding 10 seconds.

The feasibility of administering an active substance by inhalation of avapour can be demonstrated by the act of cigarette smoking. Cigarettetobacco contains up to 8% of nicotine is liberated and volatilisedduring smoking. Some nicotine will be destroyed by the high temperatureimmediately behind the burning ember. The same holds in the case ofmarijuana which may be smoked alone or in combination with tobacco. Thesmoke produced in this way contains the active component but alsocontains the products of pyrolysis, particularly tars and dustparticles. These particles may be deposited high in the respiratorytract and some of the adverse effects of cigarette smoking are due tothe deposition of carcinogenic tars at the bifurcation of the branchialtree. Here, an eddy pattern slows down the stream of inhaled particlesand causes a locally high concentration of carcinogens and otherirritants.

There is no doubt that administration by inhalation is a very effectiveway of administering some medicaments. Smoking is not, however, anacceptable way of administering medication. At a temperature greaterthan 425° F. (approximately 218° C.) cellulose and other material incigarette tobacco and paper are converted into polyaromatic hydrocarbonswhich are thought to be responsible for the carcinogenic changes in thelung. Temperatures in a burning cigarette ember may be up to 900-1,000°C. for a brief period, and between draws the temperature may still be inexcess of 400°. Burning the medication is not an efficient way ofgenerating heat.

Critical examination of the requirements for efficient administration ofmedicaments via inhalation of a vapour require a device and compositionsin which there is:

-   (i) Vaporisation at a controlled temperature;-   (ii) Generation of vapour at the time of use;-   (iii) The generated vapour is substantially free of particulate    matter;-   (iv) Control of the quantity and rate of drug delivery; Limitation    of heat so that polyaromatic hydrocarbons (PAHs) are not formed;-   (v) A quantum of heat is used in vaporisation such that when mixed    with the rest of the inspired air the lining of the respiratory    tract is not scorched.

Surprisingly, it has been found that by using an electrically heatedresistor, a quantum of heat can be applied to a unit dose of acomposition so that it yields its content as vapour into a space with adefined volume. When admixed with inspired air the charge of dilutevapour has a therapeutic effect. This is achieved without taking thetime and temperature of vaporisation above that at which PAH formationcan occur.

It has been discovered that the formation of undesirable products ofpyrolysis is not a step function occurring at a specific temperature butis a function of a time-temperature product. If the period of heating isshort, then it is possible to gain higher efficiency of vaporisation byusing higher temperatures. The quantum of heat which has been found toproduce virtually complete vaporisation of a quantity of 10 mg of anextract of cannabis was 40-60 watt seconds. No PAHs were detected by GLCanalysis following vaporisation of cannabis extract at temperatures of375° C. for a period of 5 seconds.

In preferred embodiments of the method of the invention the compositionmay be heated to temperatures in the range 100-500° C., more preferably100-400° C., more preferably 100-300° C., more preferably 150-250° C.,depending on the precise nature of the composition. It is essential thatthe composition is capable of generating a vapour which is substantiallyfree of any products of pyrolysis when heated to the chosen temperature(for the chosen period of time).

The composition is heated for a period of time which is not more than 10seconds, preferably in the range 0.1-5 seconds, and most preferablyabout 1 second, depending on the nature of the composition. Thecomposition must be capable of generating a vapour which issubstantially free of any products of pyrolysis when heated for thisperiod of time (at the chosen temperature).

Using the method of the invention therapeutic substances may beadministered to the respiratory tract as a vapour or its condensate,since it is possible that the vapour comprising or consisting of thetherapeutic substance may condense within the respiratory tract.

Compositions for use in the methods of the invention comprise one ormore therapeutic substances or precursors thereof and when heatedgenerate a vapour which may also comprise one or more therapeuticsubstances or precursors thereof. However, it is to be understood thatin many instances the “therapeutic substances or precursors thereof”present in the vapour generated by heating of a given composition maydiffer from the “therapeutic substances or precursors thereof” originalpresent in the composition in terms of chemical structure. In otherwords, it is often not the case that the vapour generated from a givencomposition is chemically identical to the original composition. Some ofthe possibilities are summarised below, however this is intended to beillustrative of rather than limiting to the invention:

The composition may comprise therapeutic substances in pharmacologicallyactive form. On heating, the composition generates a vapour which alsocomprises the therapeutic substances in pharmacologically active form.

The composition may contain a pharmacologically inactive precursor of atherapeutic substance. On heating, the precursor is converted into thecorresponding therapeutic substance by the action of heat duringvaporisation, thus giving a vapour which comprises the pharmacologicallyactive therapeutic substance.

The composition may contain a pharmacologically inactive precursor of atherapeutic substance. On heating, the composition generates a vapourwhich also comprises the precursor in pharmacologically inactive form.The precursor is converted into the pharmacologically active therapeuticsubstance in situ in the respiratory tract.

Each of the above examples results in the delivery of apharmacologically active therapeutic substance to the respiratory tract.

The term “therapeutic substance” encompasses essentially any substancewhich it is desired to administer to a human or animal subject for thepurpose of providing some therapeutic benefit to the subject.“Therapeutic benefit” in this context includes prophylactic treatmentfor the purposes of preventing disease, as well as treatment aimed atalleviating the symptoms of disease. Suitable “therapeutic substances”include conventional pharmacologically active pharmaceutical substancesand medicaments and also extracts from plants which are known to havetherapeutic activity.

The term “precursor of a therapeutic substance” refers to a substancewhich is pharmacologically inactive but is capable of being convertedinto a pharmacologically active therapeutic substance. In particular,the term “precursor of a therapeutic substance” encompasses substanceswhich are present in a pharmacologically inactive form in thecomposition but are converted into a pharmacologically active form bythe application of heat during the vaporisation process, thus giving thecorresponding “therapeutic substance” in the resultant vapour. Specificexamples include the acid forms of cannabinoids which may be convertedto the active free cannabinoid form by the application of heat duringvaporisation. Compositions comprising cannabinoid acids as precursors oftherapeutic substances thus generate vapours containing thecorresponding free cannabinoids which are therepeutic substances.

The term “precursors of therapeutic substances” is also used herein torefer to substances which are present in a pharmacologically inactiveform in the vapour generated by heating of a composition but areconverted into a pharmacologically active form in situ when introducedinto the respiratory tract.

The therapeutic substance(s), or precursor(s) thereof, generated byheating of the composition preferably have a boiling point or producesubstantial vapour pressure in the range 75° C.-500° C., more preferablyin the range 180° C.-375° C. The term “substantial vapour pressure” isdefined as meaning that the substance generates an effective amount ofvapour (preferably an amount of vapour which is sufficient to be oftherapeutic benefit when administered to a patient in admixture withinspired air) at the stated temperature.

In a preferred embodiment the therapeutic substance included in thecomposition is at least one cannabis extract.

In a most preferred embodiment of the methods of the invention thecomposition consists of at least one cannabis extract.

In the context of this application the terms “cannabis extract” or“extract from a cannabis plant”, which are used interchangeablyencompass “Botanical Drug Substances” derived from cannabis plantmaterial. A Botanical Drug Substance is defined in the Guidance forIndustry Botanical Drug Products Draft Guidance, August 2000, USDepartment of Health and Human Services, Food and Drug AdministrationCentre for Drug Evaluation and Research as: “A drug substance derivedfrom one or more plants, algae, or macroscopic fungi. It is preparedfrom botanical raw materials by one or more of the following processes:pulverisation, decoction, expression, aqueous extraction, ethanolicextraction, or other similar processes.” A botanical drug substance doesnot include a highly purified or chemically modified substance derivedfrom natural sources. Thus, in the case of cannabis, “botanical drugsubstances” derived from cannabis plants do not include highly purified,Pharmacopoeial grade cannabinoids.

A “plant extract” is an extract from a plant material as defined in theGuidance for Industry Botanical Drug Products Draft Guidance, August2000, US Department of Health and Human Services, Food and DrugAdministration Centre for Drug Evaluation and Research.

“Plant material” is defined as a plant or plant part (e.g. bark, wood,leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof)as well as exudates.

The term “Cannabis plant(s)” encompasses wild type Cannabis sativa andalso variants thereof, including cannabis chemovars which naturallycontain different amounts of the individual cannabinoids, Cannabissativa subspecies indica including the variants var. indica andvar.kafiristanica, Cannabis indica and also plants which are the resultof genetic crosses, self-crosses or hybrids thereof. The term “Cannabisplant material” is to be interpreted accordingly as encompassing plantmaterial derived from one or more cannabis plants. For the avoidance ofdoubt it is hereby stated that “cannabis plant material” includes driedcannabis biomass.

“Botanical drug substances” derived from cannabis plants include primaryextracts prepared by such processes as, for example, maceration,percolation, extraction with solvents such as C1 to C5 alcohols(ethanol), Norflurane (HFA134a), HFA227 and liquid carbon dioxide underpressure. The primary extract may be further purified for example bysupercritical or subcritical extraction, vaporisation andchromatography. When solvents such as those listed above are used, theresultant extract contains non-specific lipid-soluble material. This canbe removed by a variety of processes including “winterisation”, whichinvolves chilling to −20° C. followed by filtration to remove waxyballast, extraction with liquid carbon dioxide and by distillation.

Preferred “cannabis extracts” include those which are obtainable byusing any of the methods or processes specifically disclosed herein forpreparing extracts from cannabis plant material. The extracts arepreferably substantially free of waxes and other non-specific lipidsoluble material but preferably contain substantially all of thecannabinoids naturally present in the plant, most preferably insubstantially the same ratios in which they occur in the intact cannabisplant. In a preferred embodiment, substantially all the cannabinoidspresent in the extract will be in the same chemical form in which theyoccur in the cannabis plant, this being predominantly the cannabinoidacid form.

Botanical drug substances are formulated into “Botanical Drug Products”which are defined in the Guidance for Industry Botanical Drug ProductsDraft Guidance, August 2000, US Department of Health and Human Services,Food and Drug Administration Centre for Drug Evaluation and Research as:“A botanical product that is intended for use as a drug; a drug productthat is prepared from a botanical drug substance.”

In a further preferred embodiment the therapeutic substance included inthe composition may comprise one or more natural or syntheticcannabinoids.

In this embodiment the “cannabinoids” may be highly purified,Pharmacopoeial Grade substances and may be obtained by purification froma natural source or via synthetic means. The cannabinoids will include,but are not limited to, tetrahydrocannabinoids, their precursors, alkyl(particularly propyl) analogues, cannabidiols, their precursors, alkyl(particularly propyl) analogues, and cannabinol.

In a preferred embodiment the therapeutic substance may comprisetetrahydrocannabinol, Δ⁹-tetrahydrocannabinol, Δ⁹-tetrahydrocannabinolpropyl analogue, cannabidiol, cannabidiol propyl analogue, cannabinol,cannabichromene, cannabichromene propyl analogue, cannabigerol or anymixture thereof.

The compositions may comprise specific ratios of the cannabinoidscannabidiol (CBD) to tetrahydrocannabinol (THC). As discussed in theapplicant's co-pending application (GB 0121715.7), specific combinationsof these cannabinoids have been found to be clinically useful in thetreatment or management of specific diseases or medical conditions.

The compositions according to the invention may comprise extracts of thecannabis plant and also individual cannabinoids, or synthetic analoguesthereof, whether or not derived from cannabis plants, and alsocombinations of cannabinoids. “Cannabis plants” includes wild typeCannabis sativa and variants thereof, including cannabis chemovars whichnaturally contain different amounts of the individual cannabinoids. Inparticular, the compositions may include cannabis based medicineextracts (CBME).

Although preferred therapeutic substances include cannabis extracts andcannabinoids, the utility of the invention is by no means limited toadministration of these substances. A list of therapeutic substanceswhich may be included in the compositions of the invention andadministered in the form of a vapour according to the method of theinvention is given in table 1. TABLE 1 Therapeutic substances which canbe administered in the form of a vapour. CLASS OF MEDICAMENT EXAMPLE OFMEDICAMENT Alkaloid-rich extracts of Hyoscine Belladonna atropaHyoscamine Atropine Alkaloid-rich extracts of Gallanthamine Gallanthusspp. Alkaloid-rich extracts of Gallanthamine Narcissus spp.Alkaloid-rich extracts Morphine of opium Codeine DiamorphineAlkaloid-rich extracts of Pilocarpine salicylate PilocarpineAnti-asthmatics Terbutaline Antibacterials Chlorocresol Anti-emeticsOndansetron Prochlorperazine Antifungals Fluconazole Anti-inflammatoryagents Benzidamine Pyroxicam Antivirals Acyclovir Zidovudine SteroidBeclomethasone Cannabinoid-rich fractions of Cannabis sativa andCannabis indica, and chemovars derived from them Cannabinoids Δ⁻⁹Tetrahydrocannabinol (THC) Cannabidiol (CBD) Cannabivarins (THCV)Cannabinol (CBN) Cannabinoid-rich fractions THCA containing cannabinoidsother CBDA than THC, CBD or CBN as the most abundant componentCardiovascular Agents Nifedipine Diltiazem Verapamil Centrally actinganalgesics Butorphenol Buprenorphine Fentanyl Steroid ester Fluticasonepropionate Sympathomemetic amines Salbutamol

The compositions described herein are suitable for use and intended foruse in methods of treatment of the human or animal body by therapy. Inparticular, the compositions may be heated to produce a vapour, whichvapour (or its condensate) is then administered to the respiratory tractby inhalation.

In preferred embodiments, the invention provides compositions comprisingcannabis extracts, natural or synthetic cannabinoids or mixtures thereofwhich can be administered in the form of a vapour for the treatment ofpain, particularly pain unresponsive to opioid analgesics, pain arisingfrom neuropathic and neurogenic conditions, dysmenorrhoea, inflammatorypain, particularly that associated with rheumatoid arthritis,depression, migraine, asthma, epilepsy, post-operative pain, glaucoma,chemotherapy-induced nausea and vomiting, relief of pain and musclespasm in multiple sclerosis, and loss of appetite and anorexia,particularly in AIDS patients.

Cannabis has been used medicinally for many years, and in Victoriantimes was a widely used component of prescription medicines. It was usedas a hypnotic sedative for the treatment of “hysteria, delirium,epilepsy, nervous insomnia, migraine, pain and dysmenorrhoea”. The useof cannabis continued until the middle of the twentieth century, and itsusefulness as a prescription medicine is now being re-evaluated. Thediscovery of specific cannabinoid receptors and new methods ofadministration have made it possible to extend the use of cannabis-basedmedicines to historic and novel indications.

The recreational use of cannabis prompted legislation which resulted inthe prohibition of its use. Historically, cannabis was regarded by manyphysicians as unique; having the ability to counteract pain resistant toopioid analgesics, in conditions such as spinal cord injury, and otherforms of neuropathic pain including pain and spasm in multiplesclerosis.

In the United States and Caribbean, cannabis grown for recreational usehas been selected so that it contains a high content oftetrahydrocannabinol (THC), at the expense of other cannabinoids. In theMerck Index (1996) other cannabinoids known to occur in cannabis such ascannabidiol and cannabinol were regarded as inactive substances.Although cannabidiol was formerly regarded as an inactive constituentthere is emerging evidence that it has pharmacological activity, whichis different from that of THC in several respects. The therapeuticeffects of cannabis cannot be satisfactorily explained just in terms ofone or the other “active” constituents.

It has been shown that tetrahydrocannabinol (THC) alone produces a lowerdegree of pain relief than the same quantity of THC given as an extractof cannabis. The pharmacological basis underlying this phenomenon hasbeen investigated. In some cases, THC and cannabidiol (CBD) havepharmacological properties of opposite effect in the same preclinicaltests, and the same effect in others. For example, in some clinicalstudies and from anecdotal reports there is a perception that CBDmodifies the psychoactive effects of THC. This spectrum of activity ofthe two cannabinoids may help to explain some of the therapeuticbenefits of cannabis grown in different regions of the world. It alsopoints to useful effects arising from combinations of THC and CBD. Thesehave been investigated by the applicant. Table 2 below shows thedifference in pharmacological properties of the two cannabinoids. TABLE2 Effect THC THCV CBD CBDV Reference CB₁ (Brain receptors) ++ ± Pertweeet al, 1998 CB₂ (Peripheral + − receptors) CNS Effects Anticonvulsant †−− ++ Carlini et al, 1973 Antimetrazol − − GW Data Anti-electroshock −++ GW data Muscle Relaxant −− ++ Petro, 1980 Antinociceptive ++ + GWdata Catalepsy ++ ++ GW data Psychoactive ++ − GW data Antipsychotic −++ Zuardi et al, 1991 Neuroprotective + ++ Hampson antioxidant A J etal, activity* ++ − 1998 Antiemetic + + Sedation (reduced ++ Zuardi etal, spontaneous activity) 1991 Appetite stimulation ++ Appetitesuppression − ++ Anxiolytic GW data Cardiovascular Effects Bradycardia− + Smiley et al, 1976 Tachycardia + − Hypertension § + − Hypotension §− + Adams et al, 1977 Anti-inflammatory ± ± Brown, 1998Immunomodulatory/ anti-inflammatory activity Raw Paw Oedema − ++ GW dataTest Cox 1 GW data Cox 2 GW data TNFá Antagonism + + ++ ++ Glaucoma ++ +*Effect is CB1 receptor independent.† THC is pro convulsant§ THC has a biphasic effect on blood pressure; in naïve patients it mayproduce postural hypotension and it has also been reported to producehypertension on prolonged usage. GW Internal Report No 002/000159.

From these pharmacological characteristics and from direct experimentscarried out by the applicant it has been shown, surprisingly, thatcombinations of THC and CBD in varying proportions are particularlyuseful in the treatment of certain therapeutic conditions. It hasfurther been found clinically that the toxicity of a mixture of THC andCBD is less than that of THC alone.

Accordingly, in a further aspect the present invention providescompositions according to the invention which comprise specific ratiosof CBD to THC, and which are clinically useful in the treatment ormanagement of specific diseases or medical conditions.

In a further aspect the invention also provides compositions which havespecific ratios of tetrahydrocannabinovarin (THCV) or cannabidivarin(CBDV). THCV and CBDV (propyl analogues of THC and CBD, respectively)are known cannabinoids which are predominantly expressed in particularCannabis plant varieties and it has been found that THCV has qualitativeadvantageous properties compared with THC and CBD respectively. Subjectstaking THCV report that the mood enhancement produced by THCV is lessdisturbing than that produced by THC. It also produces a less severehangover.

In a still further aspect the invention provides compositions which havespecific ratios of THCV to THC. Such compositions have been found to beparticularly useful in the field of pain relief and appetitestimulation.

The invention also provides for administration of the above-describedcompositions containing specific ratios of cannabinoids in the form of atherapeutic vapour (or condensate) using the method of the invention.

The invention also provides methods of making a therapeutic vapour byheating of the aforementioned compositions under defined conditions, aswell as methods of using the vapour so-produced to treat or managespecific diseases or conditions.

It has particularly been observed by the present applicants that thecombinations of the specific cannabinoids are more beneficial than anyone of the individual cannabinoids alone. Preferred embodiments arethose compositions in which the amount of CBD is in a greater amount byweight than the amount of THC. Such compositions are designated as“reverse-ratio” compositions and are novel and unusual since, in thevarious varieties of medicinal and recreational Cannabis plant availableworld-wide, CBD is the minor cannabinoid component compared to THC. Inother embodiments THC and CBD or THCV and CBDV are present inapproximately equal amounts or THC or THCV are the major component andmay be up to 95.5% of the total cannabinoids present.

Particularly preferred embodiments and the target medical conditions forwhich they are suitable are shown in Table 3 below. TABLE 3 TargetTherapeutic Groups for Different Ratios of Cannabinoid Product groupRatio THC:CBD Target Therapeutic Area High THC >95:5  Cancer pain,migraine, appetite stimulation Even ratio 50:50 Multiple sclerosis,spinal cord injury, peripheral neuropathy, other neurogenic pain.Reverse/Broad <25:75  Rheumatoid arthritis, ratio CBD Inflammatory boweldiseases. High CBD <5:95 Psychotic disorders (schizophrenia), Epilepsy &movement disorders Stroke, head injury, Disease modification in RA andother inflammatory conditions Appetite suppression

A principal advantage of the method of the invention is the ability toadminister therapeutic substances in the form of a vapour which issubstantially free of the products of pyrolysis, and in particular whichis substantially free of the products of pyrolysis of vegetable matter.

Pyrolysis of vegetable matter generally occurs at about 218° C. Thus,one would assume that the maximum temperature of operation would be 218°C. This is not the case with the method of the present invention,however. The inventors have determined that because the heating time isshort (the time period envisaged is less than 10 sec, preferably 0.1 to5 sec, and most preferably about 1 sec), higher temperatures can bereached enabling compositions to be volatilised safely, without productsof pyrolysis being produced, at significantly higher temperatures thanpredicted. This opens the way for administration of many moretherapeutically active substances than one might have otherwiseenvisaged. It also offers the opportunity to include in the compositionstherapeutic substances which have a boiling point higher than 218° C.,so long as they have a boiling point or produce substantial vapourpressure at a temperature below 500° C., and more preferably below 375°C. Surprisingly, it has been found that it is possible to generatevapour from substances which have a higher boiling point than 218° C.,but which have appreciable vapour pressure at temperatures in the range130-195° C.

By selective admixture of a therapeutic substance with one or moreadditional carrier substances it is possible to reduce the temperatureat which vaporisation occurs, i.e. to reduce the “effective boilingpoint” of the therapeutic substance, such that vaporisation occurs at atemperature below the boiling point of the therapeutic substance, andalso to improve the efficiency of vapour generation.

In a preferred embodiment the compositions according to the inventionmay comprise one or more inert, non-combustible carriers or solvents, inaddition to the therapeutic substances.

Preferred inert, non-combustible carrier substances include diatomaceousearth compounds, clays, silicates, carbonates, sulphites or sulphates ofmono-dibasic metals or a mixtures thereof. Bentonite is a preferredexample. Preferred solvents include ethanol, as it will evaporate off.

In a preferred embodiment the compositions may further comprise one ormore hydrated salts which on heating release water of crystallisationand thereby modify the humidity and temperature of the vapour producedfrom the composition.

Preferred hydrated salts are pharmaceutically acceptable salts of metalsin group 1 or 2 of the Periodic table which are solids, but yield waterof crystallisation when heated. This release of water of crystallisationhas the effect of extracting latent heat and thereby reducing thetemperature of vaporisation. In addition, release of water ofcrystallisation humidifies the vapour produced by heating thecomposition and thereby improves patient acceptability.

A further advantageous feature of the invention is the possibility toinclude in the compositions non-volatile (at room temperature)pharmacologically inactive precursors of therapeutically substanceswhich can be converted into pharmacologically active, volatile forms byheating or by a change of pH.

By way of example, cannabinoids may be included in the composition inthe inactive acid form. The principal active constituents of cannabisplants, particularly Cannabis saliva and Cannabis indica, are thecannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD). Othercannabinoids such as cannabigerol (CBG), cannabichromene (CHC) and othercannabinoids are present in small quantities in harvested cannabisplants. The majority of cannabinoids are present in the plant as thecorresponding carboxylic acids. The carboxylic acids themselves havelittle or no biological activity and in the production of cannabinoidsfor medicinal use it is necessary to convert the cannabinoid acids intofree cannabinoids. Thus, when preparing extracts of cannabis formedicinal use by extraction with ethanol or supercritical CO₂ it isusual to preheat the cannabis in order to decarboxylate the cannabinoidacids to free cannabinoids.

With the present invention a separate decarboxylation step is notnecessary at any stage of the preparation of the medicinal cannabisextract, since the cannabinoid acids present in a cannabis extract maybe decarboxylated to give the active free cannabinoid form andsimultaneously vaporised by the application of heat in the vaporisationstep. This has implications for the delivery of active cannabinoids byinhalation, since it is possible to formulate a composition for deliveryof cannabinoids as a vapour from an extract from a cannabis plant inwhich the majority of the cannabinoids are present in the inactive acidform without the need for de-carboxylation of the extract.

A suitable crude cannabis extract may be prepared by solvent extractionusing a mixture of alcohol and water. The use of such mixtures reducesthe lipophilicity of the solvent system and leads to proportionatelygreater extraction of cannabinoid acids. The extraction of cannabinoidacids in progressively more dilute alcohols is increased at high pH. Thesolvent extract may be prepared using conventional techniques known inthe art such as, for example, maceration, percolation and reflux(Soxhlet) extraction.

In a further embodiment of the invention, compositions for delivery as avapour may be formed by admixture of salts of esters of alkaloids withalkali or alkaline salts. The salts and esters of alkaloids arerelatively non-volatile but when admixed with an alkali or alkaline saltare converted into the free alkaloid which is volatile. Pure compoundswhich are non-volatile in the salt form may also be converted intovolatile substances by the application of heat.

In the methods of the invention the composition is heated to a definedtemperature for a defined period of time, thereby producing a vapourcomprising the therapeutic substances, or precursors thereof. The stepof heating the composition may be carried out using any means known inthe art which are suitable for this purpose. A preferred method ofvaporisation involves placing the composition on an inert matrix orsupport which is then heated.

In a preferred embodiment, vaporisation of the composition may becarried out using a vaporiser apparatus which is the subject of aparallel application. The device consists of a heater which providesenergy to vaporise the composition. The volume of vapour so produced isless than the mean respiratory tidal volume of air of a human subjectand this charge of vapour is then admixed with inspired air during theact of breathing in. The compositions provide unit dose formulationswhich are intended for producing sufficient vapour to be taken in duringone to several breaths. The device contains a resistive element on whichthe composition is deposited and a source of electrical power which isapplied to heat the resistive element and thereby vaporise components ofthe composition. The device may further include a system of one-wayvalves which allow efficient inspiration of the vapour-laden air.

The invention will be further understood with reference to the followingnon-limiting experimental examples.

EXAMPLE 1 Preparation of a Cannabis Based Medicine Extract

2.5 Kg of dried cannabis biomass is reduced to a coarse powder andpacked into the chamber of a Supercritical Fluid Extractor and extractedfor 8 hours at a temperature of 40° C. at a pressure of 400 bar. Theresulting extract is dissolved in 2 parts (by weight) of ethanol BP,chilled to −20° C., the precipitated plant ballast removed by filtrationand evaporated to remove solvent. This extract is referred to asCannabis Based Medicine Extract (CBME) and is the Botanical DrugSubstance, used in the preparation of products in some of the followingexamples.

EXAMPLE 2 Composition for Administration of Cannabinoids by Inhalation

High THC extract of cannabis 10 parts High CBD extract of cannabis 10parts Bentonite  2 parts

Ethanol 90% BP a sufficient quantity (qs) to produce a pourablesuspension.

Portions of the suspensions are applied to an inert matrix, and allowedto dry, forming a dose unit. When the dose unit is heated at atemperature between 130° C. and 225° C. (preferably 160-180° C.) thecannabinoid is vaporised, and can be inhaled by the patient.

The suspension can be applied as discreet drops to the matrix or by ascreen-printing technique to cover the area of an electrical resistencewhich is used as the heating element. The solvent is allowed toevaporate off at room temperature.

The proportions of cannabis extract give an approximately 50/50 mix ofTHC and CBD.

EXAMPLE 3 Composition for Administration of Cannabinoids by Inhalation

High THC extract of cannabis 20 parts  Sodium sulphate decahydrate 5parts (finely powdered) Sodium Sulphite 0.5 parts   Bentonite 2 parts

Ethanol qs to produce a suspension.

The composition produced by this procedure is an example of thecomposition which has a high ratio of THC to CBD. It also containssodium sulphite as hydrated salts. When heated, the hydrated salts yieldup their water of crystallisation. The vaporisation of water withdrawsheat and serves to reduce the maximum temperature achieved, allowing ahigher initial rate of heating to be used to vaporise the medicament.The presence of water vapour also augments the volatilisation ofcannabinoids and other constituents in the extract. Sodium sulphite actsas a chemical antioxidant during storage, and during volatilization. Theamount of sulphur dioxide liberated is below that at which irritation ofthe respiratory tract occurs.

EXAMPLE 4 Composition for Administration of Cannabinoids by Inhalation

High CBD cannabis extract 20 parts  Calcium sulphate (dihydrate) 5 partsSodium carbonate decahydrate 5 partsEthanol—sufficient quantity to produce a suspension.

The composition, when applied to an inert matrix as a thin layer ordiscrete drop, dries to give a dosage form which on heating, yields avapour in which the ratio of CBD/THC is 30:1.

The examples given above are illustrative, and persons skilled in theart will appreciate that it is possible by varying the quantities ofingredients to achieve intermediate ratios of cannabinoid which may beappropriate for treatment of specific therapeutic conditions.

EXAMPLE 5 Composition for Administration of Ephedrine by Inhalation

Ephedrine sulphate 20 parts Povidone 1 part Bentonite 2 parts Sodiumphosphate (tribasic) 0.5 parts dodecahydrateAlcohol, sufficient to produce a pourable suspension.

This formulation when applied drop-wise or as a uniform film to thesurface of the substrate provides a dosage form which, when heated,produces a vapour of ephedrine. The tribasic sodium phosphate yieldswater of crystallisation which facilitates the generation of vapour.Until heated the products remains dry, and when heated the basicphosphate liberates ephedrine alkaloid from the stable form—ephedrinehydrochloride. Sufficient of the composition is present in the dosageform to give a quantity of 5-20 mg of ephedrine, by inhalation, suitablefor the treatment of asthma and other conditions requiringbronchodilation.

EXAMPLE 6 Growing of Medicinal Cannabis

Plants are grown as clones from germinated seed, under glass at atemperature of 25° C.±1.5° C. for 3 weeks in 24 hour daylight; thiskeeps the plants in a vegetative state. Flowering is induced by exposureto 12 hour day length for 8-9 weeks.

No artificial pesticides, herbicides, insecticides or fumigants areused. Plants are grown organically, with biological control of insectpests.

The essential steps in production from seed accession to dried MedicinalCannabis are summarised as follows: Seed Accessions ↓ Seeds germinatedat G-Pharm (UK) ↓ Selection for cannabinoid content and vigour ↓ MotherPlant ↓ Cuttings rooted 14-21 days in peat plug 25 C., 24 hour daylength ↓ Rooted cuttings potted up in 5 liter pots of bespoke compost ↓Young Clone Plant established 3 weeks, 24 hour day length, 25° C. ↓Lower Branches Removed end of week 3 Used to make new generation ofcuttings ↓ Induction of flowering Plant relocation to 12 hour day lengthare to induce flowering ↓ Flower formation and maturation 8-9 weeks at25° C. ↓ Harvest 90% of flowers and leaves senesced ↓ Drying Underconditions of light exclusion ↓ MEDICINAL CANNABIS

EXAMPLE 7 Preparation of Herbal Drug Extracts

A flow chart showing a process which can be used for manufacture ofextracts from High-THC and High-CBD cannabis chemovars is given below:Medicinal Cannabis (High-THC or High-CBD) ↓ Chopping to predominantly 2to 3 mm ↓ Heating at 100 to 150° C. for sufficient time to decarboxylateacid form of cannabinoids to produce neutral cannabinoids ↓ Extractionwith a specified volume of liquid carbon dioxide over 6 to 8 hours ↓Removal of CO₂ by depressurisation to recover crude extract ↓“Winterisation”-Dissolution of crude extract in ethanol Ph. Eur.followed by chilling solution (−20° C./48 hrs) to precipitate unwantedwaxes ↓ Removal of unwanted waxy material by cold filtration ↓ Removalof ethanol from the filtrate by thin film evaporation under reducedpressure

The step of heating at 100 to 150° C. for sufficient time todecarboxylate acid form of cannabinoids to produce neutral cannabinoidsmay be omitted, since cannabis medicinal extracts wherein the majorityof cannabinoids are present in the inactive acid form may beadministered directly as a vapour using the method of the invention.Decarboxylation and vaporisation to produce a therapeutic vapourcomprising the free cannabinoids may be accomplished in a singlevaporisation step.

EXAMPLE 8

High THC cannabis was grown under glass at a mean temperature of 21+2°C., RH 50-60%. Herb was harvested and dried at ambient room temperatureat a RH of 40-45% in the dark. When dry, the leaf and flower head werestripped from stem and this dried biomass is referred to as “medicinalcannabis”.

Medicinal cannabis was reduced to a coarse powder (particles passingthrough a 3 mm mesh) and packed into the chamber of a SupercriticalFluid Extractor. Packing density was 0.3 and liquid carbon dioxide at apressure of 600 bar was passed through the mass at a temperature of 35°C. Supercritical extraction is carried out for 4 hours and the extractwas recovered by stepwise decompression into a collection vessel. Theresulting green-brown oily resinous extract is further purified. Whendissolved in ethanol BP (2 parts) and subjected to a temperature of −20°C. for 24 hours a deposit (consisting of fat-soluble, waxy material) wasthrown out of solution and was removed by filtration. Solvent wasremoved at low pressure in a rotary evaporator. The resulting extract isa soft extract which contains approximately 60% THC and approximately 6%of other cannabinoids of which 1-2% is cannabidiol and the remainder isminor cannabinoids including cannabinol. Quantitative yield was 9% w/wbased on weight of dry medicinal cannabis.

A high CBD chemovar was similarly treated and yielded an extractcontaining approximately 60% CBD with up to 4% tetrahydrocannabinol,within a total of other cannabinoids of 6%.

A person skilled in the art will appreciate that other combinations oftemperature and pressure (in the range +10° C. to 35° C. and 60-600 bar)can be used to prepare extracts under supercritical and subcriticalconditions.

1. A method of making a medicament which is a vapour comprising orconsisting of at least one therapeutic substance or a precursor thereof,which method comprises heating a composition to a temperature notexceeding 500° C. for a time not exceeding 10 seconds and therebygenerating a vapour comprising or consisting of at least one therapeuticsubstance or a precursor thereof, wherein the composition isnon-volatile at 25° C. but is capable of generating a vapour comprisingat least one therapeutic substance or a precursor thereof which issubstantially free of any products of pyrolysis when heated to atemperature not exceeding 500° C. for a time not exceeding 10 seconds.2. A method of administering a vapour or its condensate comprising orconsisting of at least one therapeutic substance or a precursor thereofby inhalation, which method comprises heating a composition to atemperature not exceeding 500° C. for a time not exceeding 10 seconds togenerate a vapour comprising or consisting of at least one therapeuticsubstance or a precursor thereof in a portion of air smaller than themean respiratory tidal volume, and inhaling the vapour so-produced orits condensate in admixture with inspired air, wherein the compositionis non-volatile at 25° C. but is capable of generating a vapourcomprising at least one therapeutic substance or a precursor thereofwhich is substantially free of any products of pyrolysis when heated toa temperature not exceeding 500° C. for a time not exceeding 10 seconds.3. A method according to claim 1 or claim 2 wherein the composition isheated to a temperature in the range 100-500° C., more preferably100-400° C., more preferably 100-300° C., more preferably 150-250° C.,and wherein the composition is capable of generating a vapour which issubstantially free of any products of pyrolysis when heated to thistemperature.
 4. A method according to claim 1 or claim 2 wherein thecomposition is heated for a period of time in the range 0.1-5 seconds,and most preferably about 1 second, and wherein the composition iscapable of generating a vapour which is substantially free of anyproducts of pyrolysis when heated for this period of time.
 5. A methodaccording to claim 1 or claim 2 wherein the therapeutic substance (s)generated from the composition have a boiling point or producesubstantial vapour pressure in the range 75° C.-500° C., more preferably180° C.-375° C.
 6. A method according to claim 1 or claim 2 wherein thecomposition comprises at least one therapeutic substance or a precursorthereof.
 7. A method according to claim 6 wherein the compositioncomprises at least one precursor of a therapeutic substance which isconverted from a pharmacologically inactive form into apharmacologically active form by the application of heat.
 8. A methodaccording to claim 6 wherein the therapeutic substance included in thecomposition is at least one cannabis extract.
 9. A method according toclaim 8 wherein the composition consists of at least one cannabisextract.
 10. A method according to claim 8 wherein the cannabis extractis a solvent extract prepared by solvent extraction using a mixture ofalcohol and water.
 11. A method according to claim 8 wherein thecannabis extract has not been subject to any decarboxylation step toconvert cannabinoid acids to free cannabinoids.
 12. A method accordingto claim 6 wherein the therapeutic substance included in the compositioncomprises one or more natural or synthetic cannabinoids.
 13. A methodaccording to claim 12 wherein the therapeutic substance comprisestetrahydrocannabinol, Δ⁹-tetrahydrocannabinol, Δ⁹-tetrahydrocannabinolpropyl analogue, cannabidiol, cannabidiol propyl analogue, cannabinol,cannabichromene, cannabichromene propyl analogue, cannabigerol or anymixture thereof.
 14. A composition formulated for administration of avapour or its condensate, which vapour comprises or consists of at leastone therapeutic substance or a precursor thereof, wherein thecomposition is non-volatile at 25° C. but is capable of generating avapour comprising at least one therapeutic substance or a precursorthereof which is substantially free of any products of pyrolysis whenheated to a temperature not exceeding 500° C. for a time not exceeding10 seconds.
 15. A composition according to claim 14 wherein thecomposition is capable of generating a vapour which is substantiallyfree of any products of pyrolysis when heated to a temperature in therange 100-500° C., more preferably 200-500° C., more preferably 300-500°C., more preferably 400-500° C.
 16. A composition according to claim 14wherein the composition is capable of generating a vapour which issubstantially free of any products of pyrolysis when heated for a periodof time in the range 0.1-5 seconds, and most preferably about 1 second.17. A composition according to claim 14 wherein the therapeuticsubstance(s) generated from the composition have a boiling point orproduce substantial vapour pressure in the range 75° C.-500° C., morepreferably 180° C.-375° C.
 18. A composition according to claim 14 whichcomprises at least one therapeutic substance or a precursor thereof. 19.A composition according to claim 18 which further includes at least onesolvent or inert, non-combustible carrier.
 20. A composition accordingto claim 19 which includes as a carrier a diatomaceous earth compound, aclay, a silicate, a carbonate, sulphite or sulphate of a mono-dibasicmetal or a mixture thereof.
 21. A composition according to claim 19 orclaim 20 which includes ethanol as a solvent.
 22. A compositionaccording to claim 18 which further comprises a hydrated salt which onheating releases water of crystallisation and thereby modifies thehumidity and temperature of the vapour produced from the composition.23. A composition according to claim 22 wherein the hydrated salt is apharmaceutically acceptable salt of a metal in group 1 or 2 of thePeriodic table containing water of crystallisation.
 24. A compositionaccording to claim 18 which comprises at least one precursor of atherapeutic substance which is converted from a pharmacologicallyinactive form into a pharmacologically active form by the application ofheat.
 25. A composition according to claim 18 wherein the therapeuticsubstance is at least one cannabis extract.
 26. A composition accordingto claim 25 wherein the cannabis extract is a solvent extract preparedby solvent extraction using a mixture of alcohol and water.
 27. A methodaccording to claim 25 wherein the cannabis extract has not been subjectto any decarboxylation step to convert cannabinoid acids to freecannabinoids.
 28. A composition according to claim 18 wherein thetherapeutic substance comprises one or more natural or syntheticcannabinoids.
 29. A composition according to claim 28 wherein thetherapeutic substance comprises tetrahydrocannabinol,Δ⁹-tetrahydrocannabinol, Δ⁹-tetrahydrocannabinol propyl analogue,cannabidiol, cannabidiol propyl analogue, cannabinol, cannabichromene,cannabichromene propyl analogue, cannabigerol or any mixture thereof.30. A vapour which is obtainable by heating a composition according toclaim 14 to a temperature not exceeding 500° C. for a time not exceeding10 seconds.